α,α′-C–H-Bond Difunctionalization of Unprotected Alicyclic Amines

Abstract

A simple one-pot procedure enables the sequential, regioselective, and diastereoselective introduction of the same or two different substituents to the α- and α′-positions of unprotected azacycles. Aryl, alkyl, and alkenyl substituents are introduced via their corresponding organolithium compounds. The scope of this transformation includes pyrrolidines, piperidines, azepanes, and piperazines.

Graphical Abstract

Fully or partially saturated azacycles are ubiquitous core structures of bioactive materials.¹ The introduction of ring-substituents via the C–H bond functionalization of the parent heterocycles is a particularly attractive strategy for accessing complex amines, and is continuing to inspire the development of diverse synthetic strategies.^2,3 While numerous methods for the α-C–H bond functionalization of amines have emerged, procedures that achieve α,α′-C–H bond difunctionalization in a single operation remain rare (Scheme 1).^4–6 Selected examples include the rhodium catalyzed metal carbenoid insertion involving carbamates (Scheme 1b),^4a,c and the ruthenium catalyzed hydroalkylation of N-2-pyridylamines (Scheme 1c).^4b A rare method enabling the introduction of two different substituents is the palladium catalyzed diarylation of thioamides with boronic acids (Scheme 1d).^4d Here we report a practical one-pot approach for the α,α′-C–H bond difunctionalization of unprotected alicyclic amines (Scheme 1e). This method utilizes simple ketone oxidants and organolithium nucleophiles, without requiring the use of transition metal catalysts.

Scheme 1.

Overview of methods for amine α,α′-C–H-bond difunctionalization

We have recently reported a method for the α-C–H bond functionalization of unprotected cyclic amines.^7,8 These substrates are first converted to their corresponding lithium amides 2 (deprotonation with n-BuLi) before being exposed to a ketone oxidant (e.g., benzophenone) to form imines 3 in their monomeric forms (see Scheme 2).⁹ Addition of an organolithium nucleophile to 3 results in lithium amide 4, which, upon workup, provides an α-substituted amine product. Instead of quenching the reaction upon formation of 4, we rationalized that the addition of an appropriate ketone oxidant should lead to the formation of imine 5. Subsequent addition of a second organolithium nucleophile, followed by workup, should provide α,α′-difunctionalized amine 1 in a single operation. Indeed, we have previously shown that α-substituted lithium amides 4 can be converted to α,α′-disubstituted products 5.⁷ Conducting the α,α′-difunctionalization in a single operation would not only save one equivalent of n-BuLi base and streamline the entire operation, but possibly provide higher overall yields. Following significant optimization (see the SI for details), the scope of the transformation was established as summarized in Scheme 2. α,α′-Diphenylation was accomplished with a range of amines. Likewise, the introduction of two different substituents (aryl, heteroaryl, alkyl, and alkenyl) could be demonstrated on a range of amines. While the yields are mostly moderate and, in some cases, low, the simplicity of the approach largely compensates for this shortcoming. In all cases studied previously with a two-step approach, the present one-pot strategy provides significantly higher yields.¹⁰ For the introduction of two different substituents, we investigated possible effects based on the order of addition. Selected examples are included in Scheme 2. For product 1ah derived from pyrrolidine, introduction of phenyl followed by n-Bu resulted in a low yield but good diastereoselectivity, while introduction of n-Bu followed by phenyl provided an improved yield but at the expense of diastereoselectivity. In contrast, for 1ai derived from piperidine, introduction of the phenyl group first was found to be beneficial. For azepane-derived product 1aj, introduction of the n-Bu group first provided favorable results. For both 1ai and 1aj, the order of addition did not impact the excellent level of diastereoselectivity.

Scheme 2. Scope of the reaction.^a.

^a Reactions were performed in ether solution at −78 °C with 1 mmol of amine, n-BuLi (1 equiv), first ketone oxidant (1.05 equiv), R′–Li (1.07–1.5 equiv), second ketone oxidant (1.2–1.7 equiv), and R″–Li (1.5–2.0 equiv). See the SI for further details. ^b Benzophenone (first oxidation) and t-butyl phenyl ketone (second oxidation) were used. ^c Trifluoroacetophenone (first and second oxidation) was used. ^d While four diastereomers could potentially be formed for product 1e, we only observed trace amounts of a second diastereomer. ^e Trifluoroacetophenone (first oxidation) and t-butyl phenyl ketone (second oxidation) were used. ^f Reaction was carried out on a 0.5 mmol scale starting with the corresponding hydrochloride salt of the amine.

In summary, we have achieved the one-pot α,α′-difunctionalization of various unprotected cyclic amines. The method is operationally simple and exhibits significant synthetic utility.